The present invention is directed to novel pentacyclic steroids and novel pentacyclic D-homosteroids that have utility as anesthetics and in the treatment of disorders relating to GABA function and activity.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. GABA activates two types of receptors, the inotropic GABAA and the metabotropic GABAB receptor. Activation of the GABAB receptor by GABA causes hyperpolarization and a resultant inhibition of neurotransmitter release. The GABAA receptor subtype regulates neuronal excitability and rapid mood changes, such as anxiety, panic, and stress response. GABAA receptors are coupled to chloride ion channels; activation of the receptor induces increased inward chloride ion flux, resulting in membrane hyperpolarization and neuronal inhibition. Drugs that stimulate GABAA receptors, such as benzodiazepines and barbiturates, have anticonvulsive effects (by reducing neuronal excitability and raising the seizure threshold) as well as anxiolytic and anesthetic effects. Recently, the effect of steroids on GABAA receptors has been demonstrated. As a result, researchers are pursuing the discovery and synthesis of neuroactive steroids that act as anesthetics and/or serve to provide treatment for disorders related to GABA function.
In addition to anesthetic properties, neuroactive steroids may be used to treat disorders related to GABA function. For example, neuroactive steroids may be used as sedative-hypnotics. Progesterone, for example, exhibits benzodiazepine-like actions, inducing reduced sleep latency and increased non-REM sleep with only small changes in slow wave and REM sleep. Further, systemic administration of GABA-enhancing steroids has demonstrated anticonvulsant effects in animals. In addition, drugs that enhance GABA responses are often used to treat anxiety in humans. Thus, it might be expected that GABA-potentiating steroids would exhibit anxiolytic effects. In addition to uses as sedative-hypnotics, anticonvulsants, and anxiolytics, neuroactive steroids may be used to treat depression. Accumulating evidence suggests that patients with major depression have decreased levels of GABAergic neurosteroids, and that certain treatments for depression alter levels of these steroids. Although GABA is not typically thought to play a critical role in the biology of depression, there is evidence that low GABAergic activity may predispose to mood disorders. Finally, inhibition of NMDA receptors and enhancement of GABAA receptors appear to play important roles in mediating the acute effects of ethanol in the nervous system. Recent studies suggest that GABAergic neurosteroids may be involved in some of the pharmacological effects of ethanol and that neuroactive steroids may be useful in treating ethanol withdrawal.
An alternative to developing GABAergic anesthetics is to focus on steroids that inhibit NMDA receptors. However, steroids that inhibit NMDA receptors often block GABAA receptors as well, resulting in complex effects on CNS excitability. Neuroactive steroids containing a 3β-sulfate group inhibit GABAA receptors non-competitively. These agents act by enhancing GABAA receptor desensitization and display different degrees of enantioselectivity. These compounds may be useful as memory enhancers and in reversing the anesthetic effects of compounds that potentiate GABA at GABAA receptors.